Never Seen Before: How Cells Behave In 3D and Real Time inside Living Organisms with Amazing Clarity (Videos and Photos)
Merging lattice light sheet microscopy with adaptive optics reveals the most detailed picture yet of subcellular dynamics in multicellular organisms.
The work — a collaboration between researchers at Howard Hughes Medical Institute, Boston Children’s Hospital and Harvard Medical School — is detailed in a new paper just published in Science.
“For the first time, we are seeing life itself at all levels inside whole, living organisms,” said Tom Kirchhausen, PhD, co-author on the new study, who is a senior investigator in the Program in Cellular and Molecular Medicine at Boston Children’s Hospital and a professor of cell biology and pediatrics at Harvard Medical School (HMS).
Credit: HHMI
Seeing is believing: Here’s what the new microscope can do
So far, the team has been taking a close look at developing zebrafish because the fish have translucent skin, making it easy to capture microscopic images of their organs and tissues in vivo.
Co-first author on the study, Gokul Upadhyayula, PhD, an instructor in pediatrics at Boston Children’s and HMS, explained that zebrafish can be genetically modified so that human disease models can be studied. Already, the team has used the microscope to watch metastatic human breast cancer cells move around inside a zebrafish, revealing new insights into how cancer spreads through living tissues.
By combining two imaging technologies, scientists can now watch in unprecedented 3-D detail as cancer cells crawl, spinal nerve circuits wire up, and immune cells cruise through a zebrafish’s inner ear.
Physicist Eric Betzig, a group leader at the Howard Hughes Medical Institute’s Janelia Research Campus, and colleagues report the work April 19, 2018, in the journal Science.
Here are neural progenitor cells from a region in the developing brain of a zebrafish embryo. The cells are expressing different colored fluorescent markers that reveal the spatial distribution of sub-cellular organelles. The cells are expressing markers for organelles including: cell membrane (grey), the Golgi apparatus (neon green), endoplasmic reticulum (magenta) and mitochondria (aqua). Although this image was taken of a whole, living zebrafish, the image was then computationally separated to allow better analysis of how each individual cell is composed.
Credit: HHMI
Scientists have imaged living cells with microscopes for hundreds of years, but the sharpest views have come from cells isolated on glass slides. The large groups of cells inside whole organisms scramble light like a bagful of marbles, Betzig says. “This raises the nagging doubt that we are not seeing cells in their native state, happily ensconced in the organism in which they evolved.”
Even when viewing cells individually, the microscopes most commonly used to study cellular inner workings are usually too slow to follow the action in 3-D. These microscopes bathe cells with light thousands to millions of times more intense than the desert sun, Betzig says. “This also contributes to our fear that we are not seeing cells in their natural, unstressed form.
“It’s often said that seeing is believing, but when it comes to cell biology, I think the more appropriate question is, ‘When can we believe what we see?’” he adds.
The new microscope is essentially three microscopes in one: an adaptive optical system to maintain the thin illumination of a lattice light sheet as it penetrates within an organism, and another adaptive optical system to create distortion-free images when looking down on the illuminated plane from above. By shining a laser through either pathway, the researchers create a bright point of light within the region they wish to image. The distortions in the image of this “guide star” tell the team the nature of the optical aberrations along either pathway. The researchers can correct these distortions by applying equal but opposite distortions to a pixelated light modulator on the excitation side, and a deformable mirror on detection. Over large volumes, the distortions change as the light traverses different tissues. In this case, the team assembles large 3-D images from a series of subvolumes, each with its own independent excitation and detection corrections.
Credit: HHMI Howard Hughes Medical Institute / Credit: T. Liu et al./Science 2018
The results offer an electrifying new look at biology, and reveal a bustling metropolis in action at the subcellular level. In one movie from the microscope, a fiery orange immune cell wriggles madly through a zebrafish’s ear while scooping up blue sugar particles along the way. In another, a cancer cell trails sticky appendages as it rolls through a blood vessel and attempts to gain purchase on the vessel wall.
All this detail is hard to see without adaptive optics, Betzig says. “It’s just too damn fuzzy.” In his view, adaptive optics is one of the most important areas in microscopy research today, and the lattice light sheet microscope, which excels at 3-D live imaging, is the perfect platform to showcase its power. Adaptive optics hasn’t really taken off yet, he says, because the technology has been complicated, expensive, and until now, not clearly worth the effort. But within 10 years, Betzig predicts, biologists everywhere will be on board.
The next big step is making that technology affordable and user-friendly. “Technical demonstrations and publications don’t amount to a hill of beans. The only metric by which a microscope should be judged is how many people use it, and the significance of what they discover with it,” Betzig says.
According to an HHMI press release, Betzig believes that adaptive optics is one of the most important areas in microscopy research today, and the lattice-light-sheet microscope, which excels at 3-D live imaging, is the perfect platform to showcase its power.
New Microscope Captures Detailed 3-D Movies of Cells Deep Within Living Systems
Credit: HHMI Howard Hughes Medical Institute /
“If you really want to understand the cell in vivo, and image it with the quality possible in vitro, this is the price of admission,” he says.
Additional authors on the paper are researchers from Stony Brook University, University of California, Berkeley, California Institute of Technology and the University of Exeter.
This work was supported by the Howard Hughes Medical Institute, the National Institutes of Health (R01GM075252, R01DC015478, 5R00CA154870-05, 1R01GM121597-01, R01CA196884 and R35GM118149), the National Science Foundation (IOS1452928), the Carol M. Baldwin Breast Cancer Research Fund, the Damon Runyon Cancer Research Foundation, Pew Charitable Trusts, Biogen, Ionis Pharmaceuticals and a Human Frontier Science Program fellowship.
Erin Tornatore
Meghan Rosen
Howard Hughes Medical Institute
Citation: Tsung-Li Liu, Srigokul Upadhyayula, Daniel E. Milkie, Ved Singh, Kai Wang, Ian A. Swinburne, Kishore R. Mosaliganti, Zach M. Collins, Tom W. Hiscock, Jamien Shea, Abraham Q. Kohrman, Taylor N. Medwig, Daphne Dambournet, Ryan Forster, Brian Cunniff, Yuan Ruan, Hanako Yashiro, Steffen Scholpp, Elliot M. Meyerowitz, Dirk Hockemeyer, David G. Drubin, Benjamin L. Martin, David Q. Matus, Minoru Koyama, Sean G. Megason, Tom Kirchhausen, Eric Betzig, “Observing the Cell in Its Native State: Imaging Subcellular Dynamics in Multicellular Organisms.” Science. Published online April 19, 2018.
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